Immunotherapy refers to modulating a person's immune responses to impart a desirable therapeutic effect. Immunotherapeutics refer to those compositions which, when administered to an individual, modulate the individual's immune system sufficient to ultimately decrease symptoms which are associated with undesirable immune responses or to ultimately alleviate symptoms by increasing desirable immune responses. In some cases, immunotherapy is part of a vaccination protocol in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response in such cases, the immunotherapeutic increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
Vaccine protocols can be improved by the delivery of agents that modulate a person's immune responses to induce an improved immune response. In some vaccination protocols in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response, an agent is provided that increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
Vaccines are useful to immunize individuals against target antigens such as allergens, pathogen antigens or antigens associated with cells involved in human diseases. Antigens associated with cells involved in human diseases include cancer-associated tumor antigens and antigens associated with cells involved in autoimmune diseases.
In designing such vaccines, it has been recognized that vaccines that produce the target antigen in cells of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use avirulent vectors, and DNA vaccines each lead to the production of antigens in the cell of the vaccinated individual which results in induction of the cellular arm of the immune system. On the other hand, killed or inactivated vaccines, and sub-unit vaccines which comprise only proteins do not induce good cellular immune responses although they do induce an effective humoral response.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines that produce the target antigen in cells of the vaccinated individual such as live attenuated vaccines, recombinant vaccines that use avirulent vectors and DNA vaccines are often preferred.
The generation of potent CD8+ T cell responses by DNA vaccine technology is a goal sought by DNA vaccine developers. There are reports that CD8+ T cells contribute to controlling viral replication in both human (Koup et al., 1994; Cao et al., 1995; Musey et al., 1997; Ogg et al., 1998; Betts et al., 1999) and non human primate models (Jin et al., 1999; Schmitz et al., 1999; Barouch et al., 2000; Amara et al., 2001; Shiver et al., 2002) in the HIV model as well as other viral infections.
Many different strategies have been used along with DNA vaccine technology, including improved delivery techniques, enhanced construct design, heterologous prime-boost strategies, and the use of molecular adjuvants. Molecular adjuvants including chemokines and cytokines can be incorporated into a vaccine strategy to skew the immune response towards cellular or humoral immunity. Cytokines such as IL-12 and IL-15 have been effective in enhancing the immune response in both murine and non-human primate models (Morrow and Weiner, 2008).
Interleukin-15 (IL-15) has been shown to play a role in the generation and maintenance of CD8+ T cells as it signals through the common βγ chain, which is also utilized by IL-2. IL-15 has been shown to be trans-presented on the surface of antigen presenting cells via IL-15Rα during the priming of Natural Killer and CD8+ T cells (Dubois et al., 2002; Koka et al., 2004; Lucas et al., 2007; Sato et al., 2007). IL-15Rα has also recently been shown to play a role in the regulation of IL-15 secretion (Duitman et al., 2008). This cell surface complex is thought to allow IL-15 to signal thorough the βγ receptor on memory CD8+ T cells promoting cell division and survival of these cells (Lodolce et al., 1998; Kennedy et al., 2000; Lodolce et al., 2001; Burkett et al., 2003; Burkett et al., 2004; Sandau et al., 2004; Schluns et al., 2004a; Schluns et al., 2004b). IL-15 and IL-15Rα together as a complex exhibit enhanced stability and secretion compared to either molecule alone (Bergamaschi et al., 2008).
In regards to its employment in vaccination models, the use of plasmid-encoded IL-15 as an HIV-1 vaccine adjuvant has been previously reported to enhance cytolytic and memory CD8+ T cell responses in mice (Oh et al., 2003; Kutzler et al., 2005; Zhang et al., 2006; Calarota et al., 2008; Li et al., 2008). Studies in rhesus macaques have also shown the ability of IL-15 to enhance effector functions of CD4+ T cells (Picker et al., 2006) and rescued dual IFN-γ/TNF responses in both effector CD4+ and CD8+ T cells (Halwani et al., 2008). Importantly, addition of pIL-15 with SIV/HIV antigens in rhesus macaques resulted in enhanced protection after SHIV89.6p challenge (Boyer et al., 2007).
While such vaccines are often effective to immunize individuals prophylactically or therapeutically against pathogen infection or human diseases, there is a need for improved vaccines. There is a need for compositions and methods that produce an enhanced immune response. There still remains a need for improved strategies to enable effective DNA vaccines, including new adjuvants that enhance the immune response to DNA vaccines.
Likewise, while some immunotherapeutics are useful to modulate immune response in a patient there remains a need for improved immunotherapeutic compositions and methods.